New insights in systemic lupus erythematosus: From regulatory T cells to CAR-T-cell strategies
Authors: Matteo Doglio, Tobias Alexander, Nicoletta Del Papa, John A. Snowden, Raffaella Greco
Journal: Journal of Allergy and Clinical Immunology (2022)

Systemic lupus erythematous is a heterogeneous autoimmune disease with potentially multiorgan damage. Its complex etiopathogenesis involves genetic, environmental, and hormonal factors, leading to a loss of self-tolerance with autoantibody production and immune complex formation. Given the relevance of autoreactive B lymphocytes, several therapeutic approaches have been made targeting these cells. However, the disease remains incurable, reflecting an unmet need for effective strategies. Novel therapeutic concepts have been investigated to provide more specific and sustainable disease modification compared with continued immunosuppression. Autologous hematopoietic stem cell transplantation has already provided the proof-of-concept that immunodepletion can lead to durable treatment-free remissions, albeit with significant treatment-related toxicity. In the future, chimeric antigen receptor-T-cell therapies, for example, CD19 chimeric antigen receptor-T, may provide a more effective lymphodepletion and with less toxicity than autologous hematopoietic stem cell transplantation. An emerging field is to enhance immune tolerance by exploiting the suppressive capacities of regulatory T cells, which are dysfunctional in patients with systemic lupus erythematous, and thus resemble promising candidates for adoptive cell therapy. Different approaches have been developed in this area, from polyclonal to genetically engineered regulatory T cells. In this article, we discuss the current evidence and future directions of cellular therapies for the treatment of systemic lupus erythematous, including hematopoietic stem cell transplantation and advanced regulatory T-cell–based cellular therapies. Systemic lupus erythematous is a heterogeneous autoimmune disease with potentially multiorgan damage. Its complex etiopathogenesis involves genetic, environmental, and hormonal factors, leading to a loss of self-tolerance with autoantibody production and immune complex formation. Given the relevance of autoreactive B lymphocytes, several therapeutic approaches have been made targeting these cells. However, the disease remains incurable, reflecting an unmet need for effective strategies. Novel therapeutic concepts have been investigated to provide more specific and sustainable disease modification compared with continued immunosuppression. Autologous hematopoietic stem cell transplantation has already provided the proof-of-concept that immunodepletion can lead to durable treatment-free remissions, albeit with significant treatment-related toxicity. In the future, chimeric antigen receptor-T-cell therapies, for example, CD19 chimeric antigen receptor-T, may provide a more effective lymphodepletion and with less toxicity than autologous hematopoietic stem cell transplantation. An emerging field is to enhance immune tolerance by exploiting the suppressive capacities of regulatory T cells, which are dysfunctional in patients with systemic lupus erythematous, and thus resemble promising candidates for adoptive cell therapy. Different approaches have been developed in this area, from polyclonal to genetically engineered regulatory T cells. In this article, we discuss the current evidence and future directions of cellular therapies for the treatment of systemic lupus erythematous, including hematopoietic stem cell transplantation and advanced regulatory T-cell–based cellular therapies. Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, characterized by a loss of self-tolerance with autoantibody production, cellular-tissue infiltration, and end-organ damage that can potentially lead to serious organ complications and even death.1Tsokos G.C. Systemic lupus erythematosus.N Engl J Med. 2011; 365: 2110-2121Crossref PubMed Google Scholar It affects women of childbearing age, with a female to male ratio of about 9:1 commonly reported.2Alexander T. Hedrich C.M. Systemic lupus erythematosus – are children miniature adults?.Clin Immunol. 2022; 234108907Crossref PubMed Scopus (1) Google Scholar The overall disease prevalence ranges from 20 to 150 per 100,000, and both incidence and prevalence of SLE are continuously increasing with substantial geographical variability.3Carter E.E. Barr S.G. Clarke A.E. The global burden of SLE: prevalence, health disparities and socioeconomic impact.Nat Rev Rheumatol. 2016; 12: 605-620Crossref PubMed Scopus (215) Google Scholar The mortality of the disease has continuously improved in recent years due to the improved understanding of the pathogenesis and advances in therapy, resulting in a 15-year survival of currently 85% to 95%.4Tektonidou M.G. Lewandowski L.B. Hu J. Dasgupta A. Ward M.M. Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016.Ann Rheum Dis. 2017; 76: 2009-2016Crossref PubMed Scopus (105) Google Scholar,5Yen E.Y. Shaheen M. Woo J.M.P. Mercer N. Li N. McCurdy D.K. et al.46-year trends in systemic lupus erythematosus mortality in the United States, 1968 to 2013.Ann Intern Med. 2017; 167: 777Crossref PubMed Scopus (0) Google Scholar Nevertheless, despite these advances, SLE is still associated with a major burden with differential impact on populations, economic costs, and health-related quality of life. Hence, there is an ongoing and unmet need for novel, disease-specific, effective and safe treatment approaches. The immunopathogenesis of SLE is complex and involves genetic, environmental, hormonal, epigenetic, and immunoregulatory factors that act either sequentially or simultaneously on the immune system.1Tsokos G.C. 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B cells contribute to the immunopathogenesis of SLE via multiple mechanisms. As progenitors of plasma cells, they are central in the generation of pathogenic autoantibodies. In addition, they mediate deleterious functions through antigen presentation to T cells, costimulatory functions via the expression of accessory molecules engaging stimulatory receptors on T cells, and the production of cytokines.10Shen P. Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines.Nat Rev Immunol. 2015; 15: 441-451Crossref PubMed Scopus (284) Google Scholar The marked B-cell hyperactivity in SLE is reflected by the presence of peripheral blood CD19+CD20−CD27++ plasmablasts that correlate with disease activity and serum anti–double-stranded DNA autoantibody titers.11Odendahl M. Jacobi A. Hansen A. Feist E. Hiepe F. 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Fuchs S. et al.Deep phenotyping of CD11c+ B cells in systemic autoimmunity and controls.Front Immunol. 2021; 12: 659Crossref Scopus (8) Google Scholar that have been associated with autoreactivity,15Wang S. Wang J. Kumar V. Karnell J.L. Naiman B. Gross P.S. et al.IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE.Nat Commun. 2018; 9: 1758Crossref PubMed Scopus (229) Google Scholar as well as CD19lowCXCR5−CD21− B cells, characteristic for extrafollicular generation.16Szelinski F, Stefanski AL, Wiedemann A, Schrezenmeier E, Rincon-Arevalo H, Reiter K, et al. Antigen-experienced CXCR5-CD19 low B cells are plasmablast precursors expanded in SLE [published online ahead of print April 20, 2022]. Arthritis Rheumatol. https://doi.org/10.1101/2021.05.25.21257784Google Scholar These memory B-cell subsets share functional properties and transcriptomic signatures with plasmablasts, suggesting their contribution to autoantibody production. In addition, B cells obtained from patients with SLE have altered expression profiles of regulatory checkpoint molecules, such as B- and T-lymphocyte attenuator (BTLA),17Wiedemann A. Lettau M. Weißenberg S.Y. Stefanski A.-L. Schrezenmeier E.-V. Rincon-Arevalo H. et al.BTLA expression and function are impaired on SLE B cells.Front Immunol. 2021; 12: 1402Crossref Scopus (6) Google Scholar and display intrinsic abnormalities in signal transduction and immunometabolism.18Zhang X. Yang Y. Jing L. Zhai W. Zhang H. Ma Q. et al.Pyruvate kinase M2 contributes to TLR-mediated inflammation and autoimmunity by promoting Pyk2 activation.Front Immunol. 2021; 12: 1655Google Scholar Once activated, memory B cells differentiate into plasmablasts that subsequently migrate to the bone marrow or inflamed tissue to become long-lived memory plasma cells. In SLE, pathogenic autoantibodies are secreted from both subsets. Short-lived plasma cells are usually associated with lupus flares,11Odendahl M. Jacobi A. Hansen A. Feist E. Hiepe F. Burmester G.R. et al.Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus.J Immunol. 2000; 165: 5970-5979Crossref PubMed Google Scholar whereas long-lived plasma cells contribute to the disease chronicity by the continuous secretion of autoantibodies.19Hiepe F. Dörner T. Hauser A.E. Hoyer B.F. Mei H. Radbruch A. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation.Nat Rev Rheumatol. 2011; 7: 170-178Crossref PubMed Scopus (259) Google Scholar In addition to B-cell disturbances, T cells seem to be central in lupus pathology. Particularly, expanded populations of CD4+ T follicular-helper and T peripheral helper cells facilitate B-cell activation and autoantibody production,20Liarski V.M. Kaverina N. Chang A. Brandt D. Yanez D. 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Overarching treatment principles indicate that the treatment of patients should be adapted to multiple disease-specific and patient-specific aspects, especially the individual profile of involved organ manifestations, and should be based on a shared decision.37Dörner T. Furie R. Novel paradigms in systemic lupus erythematosus.Lancet. 2019; 393: 2344-2358Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Current therapeutic concepts for SLE primarily focus on a chronic suppression of autoreactive immune responses, which may be achieved by conventional immunosuppressive or biologic disease-modifying therapies, targeting cellular or soluble components involved in lupus immunopathology. Because of the complexity of the underlying immune dysregulation in SLE, usually a multitarget therapeutic approach is required to control symptoms and halt progression.37Dörner T. Furie R. Novel paradigms in systemic lupus erythematosus.Lancet. 2019; 393: 2344-2358Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Nevertheless, although providing more specificity and efficacy, these disease-modifying therapies have to be administered continuously or repeatedly, which may be associated with the cumulative risk of infectious complications or comorbidity, and are cost-effective. Alternatively, high-dose immunosuppression followed by hematopoietic stem cell transplantation (HSCT) has emerged as an effective on/off therapy that has the capacity to provide long-term, treatment-free remissions, indicating that the resetting of the immune system by depleting autoreactive immunologic memory cells with a consecutive reinduction of immunologic self-tolerance has curative potential.37Dörner T. Furie R. 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For patients with severe organ involvement and insufficient response to either mycophenolate mofetil or CYC, treatment with rituximab is recommended, despite negative results from randomized controlled trials. The only biologic therapy recommended with a grade A recommendation is the B-cell–activating factor–targeting mAb belimumab, which demonstrated efficacy in both renal41Furie R. Rovin B.H. Houssiau F. Malvar A. Teng Y.K.O. Contreras G. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (251) Google Scholar and nonrenal lupus manifestations.42Furie R. Petri M. Zamani O. Cervera R. Wallace D.J. Tegzová D. et al.A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.Arthritis Rheum. 2011; 63: 3918-3930Crossref PubMed Scopus (1037) Google Scholar In addition, the IFN-α receptor–targeting antibody anifrolumab was recently approved as add-on biologic therapy for SLE,43Morand E.F. Furie R. Tanaka Y. Bruce I.N. Askanase A.D. Richez C. et al.Trial of anifrolumab in active systemic lupus erythematosus.N Engl J Med. 2020; 382: 211-221Crossref PubMed Scopus (414) Google Scholar as well as the novel calcineurin inhibitor voclosporin for lupus nephritis.44Rovin B.H. Teng Y.K.O. Ginzler E.M. Arriens C. Caster D.J. 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Snowden J.A. Hematopoietic stem cell transplantation for autoimmune disease.Annu Rev Med. 2021; 72: 215-228Crossref PubMed Scopus (17) Google Scholar The basic principle of HSCT is to achieve a broad immune depletion, providing an initial "debulking" of the immunologic memory repertoire, including memory T and B lymphocytes as well as plasma cells that are usually refractory to standard immunosuppression but sensitive to conditioning treatment with anti–thymocyte globulin,53Zand M.S. Vo T. Pellegrin T. Felgar R. Liesveld J.L. Ifthikharuddin J.J. et al.Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin.Blood. 2006; 107: 2895-2903Crossref PubMed Scopus (73) Google Scholar followed by regeneration of the hematopoietic and immune systems.54Alexander T. Arnold R. Hiepe F. Radbruch A. Resetting the immune system with immunoablation and autologous haematopoietic stem cell transplantation in autoimmune diseases.Clin Exp Rheumatol. 2016; 34: 53-57PubMed Google Scholar,55Swart J.F. Delemarre E.M. van Wijk F. Boelens J.-J. Kuball J. van Laar J.M. et al.Haematopoietic stem cell transplantation for autoimmune diseases.Nat Rev Rheumatol. 2017; 13: 244-256Crossref PubMed Scopus (87) Google Scholar To date, more than 300 patients have received autologous HSCT specifically for SLE. Between 1996 and 2020, 112 patients with SLE have been reported within the European Society for Blood and Marrow Transplantation (EBMT) registry (Fig 2). Pooled data from the largest 15 single-center experiences and multicenter trials with 339 patients included indicate a disease-free survival of 50% to 66% at 5 years despite discontinuation of immunosuppressive and other targeted disease-modifying therapies.56Burt R.K. Farge D. Ruiz M.A. Saccardi R. Snowden J.A. Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases. CRC Press, Boca Raton2021Crossref Google Scholar Notably, treatment-related mortality gradually declined from 12% in the first EBMT registry survey in 2004 to less than 5% in most recent reports between 2017 and 2019. Responding patients are usually free of clinical symptoms and may regain seronegativity for antinuclear antibodies, a state referred to as complete clinical and serologic remission "off therapy," which is rarely seen under conventional therapies.35van Vollenhoven R. Voskuyl A. Bertsias G. Aranow C. Aringer M. Arnaud L. et al.A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).Ann Rheum Dis. 2017; 76: 554-561Crossref PubMed Scopus (199) Google Scholar Compared with continued insufficient or failed chronic immunosuppression, early use of HSCT has also the potential to protect against organ failure and toxicity-related morbidity, such as cardiovascular events, infections, and secondary malignancy, and improve quality of life.57Burt R.K. Han X. Gozdziak P. Yaung K. Morgan A. Clendenan A.M. et al.Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome.Bone Marrow Transplant. 2018; 53: 692-700Crossref PubMed Scopus (15) Google Scholar According to previous